The ongoing advances in medicine and biotechnology are providing many effective and promising systemic therapies that call for the delivery of biological and chemical substances (such as peptides, proteins, and small molecules) to the patient's bloodstream. There are various problems associated with getting certain substances to the bloodstream by conventional delivery means, such as transdermal and oral. For instance, oral delivery of therapeutic proteins does not work because the proteins are digested before they have an opportunity to reach the bloodstream. Thus, for this and other reasons, it is best to deliver such substances to the bloodstream by as direct a route as possible.
An aerosol is a gaseous suspension of very fine solid or liquid particles. Aerosols are presently used for delivering certain drugs to a patient's lungs. Delivery of drugs or other therapeutic substances to a patient's lungs is sometimes referred to as pulmonary delivery.
The innermost tissue of the lung is know as the alveolar epithelium, which comprises hundreds of millions of tiny air sacs, called alveoli, that are surrounded by a large network of blood capillaries. The alveoli walls are a thin, single cellular layer that enables rapid absorption of fluids from the alveoli to the bloodstream. Most effective pulmonary delivery is accomplished when the substance is delivered to the alveoli. The delivery process requires the generation of very small particles or droplets that can be entrained in a gas as an aerosol and inhaled by the patient into the alveoli for transfer to the bloodstream.
The lung's alveoli can readily absorb liquid drops having diameters of about 4 μm, which represents a volume of 33.5 femtoliters. A femtoliter is one quadrillionth (10−15) of a liter. Larger drops tend to contact the lung walls before reaching the alveoli and are less likely to permeate the wall to the bloodstream because the airway to the alveoli is lined with a thick, ciliated mucus-covered cell layer.
A popular pulmonary delivery mechanism is known as a metered dose inhaler (MDI). These are widely used for the delivery of asthma medication. While an MDI delivery system may be effective for medications designed to medicate the lung tissue, they are not optimal for delivery of substances to the alveoli (hence, to the bloodstream). In this regard, an MDI typically combines the drug with a propellant in a pressurized container. Actuation of the device releases metered doses of the aerosol, but the droplet size distribution is large, and the vapor pressure of the propellant varies with temperature and number of uses. Thus, the behavior of the material in the air stream and the extent to which droplets reach the alveoli becomes somewhat unpredictable.
In view of the foregoing, it can be appreciated that there is a need for a droplet generator that can reliably produce very small-volume droplets with a generally uniform size distribution for entrainment in aerosols.
One reference, U.S. Pat. No. 5,894,841, has recognized the potential of generating very small droplets using a drop generator that is adapted from the kind employed in ink-jet printing. The type of ink-jet printing of interest here (often called thermal ink-jet printing) conducts ink into tiny chambers. Each chamber includes a heat transducer such as, for example, a thin-film resistor to create a vapor bubble that ejects a droplet of ink through an orifice that overlies the chamber. The chambers and orifices are incorporated into a printhead device that is connected with a supply of ink and with a controller for timing the droplet ejection to reproduce images on media. The just-mentioned reference does not provide particulars of a thermally efficient drop generator for creating the femtoliter-size drops that are desirable for effective pulmonary delivery.
As respects drop generators such as those used with thermal ink-jet printing, orifice size is but one factor for controlling the size of the droplet volume that is expelled with each activation of the resistor (or other suitable heat transducer). Much greater roles are played by the configuration of the ink chamber that is associated with the orifice, as well as the size and energy-producing capabilities of the heat transducer in the chamber.
Current ink-jet designs provide drop generators that produce droplet volumes as small as 4 picoliters, which is equivalent to 4,000 femtoliters. In order to produce droplets in the range of tens of femtoliters that can be entrained, for example, in an aerosol for delivery of the droplets to the alveoli, one is confronted with several problems that prevent a simple scaling-down of current designs to arrive at such small droplet volumes.
For example, ejection of single droplets in the tens of femtoliters size range would require extremely small ink chambers and resistors, having critical dimensions that would be difficult to fabricate and control with conventional ink-jet printhead manufacturing processes. Even if such fabrication were undertaken, such small resistors would likely be thermally inefficient. The heat loss (that is, energy not transferred to the ink in the course of forming a vapor bubble) from such small resistors would have to be overcome with a relatively higher amount of energy (called turn-on-energy, or TOE) for forming the vapor bubble. Increasing the TOE generates more stress in the heat transducer, which tends to lower reliability of the transducer over time.
The present invention is directed to a thermal-type drop generator having a geometry that is configured so that the ejection of the liquid from the chamber has the effect of separating the ejected volume into a number of small droplets. This provides a thermally efficient drop generator (as compared to one that is scaled to produce a single small droplet for each activation of the heat transducer) and generally avoids the need for meeting difficult manufacturing tolerances as discussed above.
In one preferred embodiment of the present invention the relationship between the thickness of the liquid chamber and the area of the heat transducer is controlled to provide the separating aspect mentioned above.
The ejection of the liquid is readily controlled for precise metering of the amount of droplets ejected. It will be appreciated, therefore, that the thermal generation of droplets contemplated by the present invention provides in a single action (that is, the controlled “firing” of the heat transducer to expel the contents of the liquid chamber) both the metering of the amount of liquid expelled, as well as the generation of suitably small droplets. That is, the firing of liquid from the chamber need not be accompanied with other mechanisms for reducing the volume of ejected liquid to suitably small droplets.
As another aspect of this invention, the volume of liquid in a chamber is expelled through a number of orifices using the volume-separating aspect mentioned above. This has the effect of multiplying (relative to a single-orifice embodiment) the number of droplets produced each time the heat transducer is activated. 
Apparatus and methods for carrying out the invention are described in detail below. Other advantages and features of the present invention will become clear upon review of the following portions of this specification and the drawings.